title: Cytotoxic tetramic acid derivative produced by a plant type-III polyketide synthase.
abstract: The tetramic acid (2,4-pyrrolidinedione) scaffold has been recognized as an important structural feature because of its mycotoxic, antibacterial, antiviral, and antioxidant activities. This important class of natural products is reportedly produced by the type-I polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS) hybrid megaenzyme systems. In contrast, the benzalacetone synthase (BAS) from Rheum palmatum is a structurally simple, plant-specific type-III PKS that catalyzes the one-step decarboxylative condensation of malonyl-CoA with 4-coumaroyl-CoA. The type-III PKS exhibits unusually broad substrate specificity and notable catalytic versatility. Here we report that R. palmatum BAS efficiently produces a series of unnatural, novel tetramic acid derivatives by the condensation of malonyl-CoA with aminoacyl-CoA thioesters chemically synthesized from L- and D-amino acids. Remarkably, the novel tetramic acid dimer D-5 formed from D-phenylalanoyl-CoA showed moderate antiproliferative activity against murine leukemia P388 cells.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-0033, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Wakimoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Morita
authors.forename: Ikuro
authors.initials: I
authors.lastname: Abe
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D055162:Biocatalysis; D001685:Biological Factors / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D048630:Polyketide Synthases / Q000737:chemistry / Q000378:metabolism*; D011760:Pyrrolidinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012250:Rheum / Q000737:chemistry* / Q000201:enzymology / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001685:Biological Factors; D011760:Pyrrolidinones; C009435:tetramic acid; D048630:Polyketide Synthases